4-[(5-bromo-2-chlorophenyl)methyl]phenol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-(5-bromo-2-chlorobenzyl)phenol (56.7 g, 210 mmol) and Cs2CO3 (135 g, 420 mmol) in DMF (350 mL) was stirred at room temperature for 30 min, and then 2-cyclopropoxyethyl 4-methylbenzenesulfonate (crude intermediate BP from the second preceeding step above) (53.3 g, 210 mmol) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with water (3 L) and extracted with EtOAc. The organic layer was washed with water, then with brine, and dried over Na2SO4. The residue was concentrated and then purified by flash column chromatography on silica gel (eluent PE:EA=10:1) to give intermediate DK as a liquid (51 g, yield 64%). 1H NMR (CDCl3, 400 MHz): δ 7.22˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.86 (t, J=4.8 Hz, 2H), 3.38-3.32 (m, 1H), 0.62-0.66 (m, 2H), 0.49-0.52(m, 2H). was added The reaction mixture was stirred at room temperature overnight extracted with EtOAc The organic layer was washed with water with brine, and dried over Na2SO4 The residue was concentrated purified by flash column chromatography on silica gel (eluent PE:EA=10:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (intermediate B) (747 g, 2.31 mol) in dichloromethane was added slowly boron tribromide (1.15 kg, 4.62 mol) at −78° C. The reaction mixture was allowed to warm to room temperature. When the reaction was complete as measured by TLC, the reaction was quenched with water. The mixture was extracted with dichloromethane. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, then with water, and then with brine, and dried over Na2SO4. The residue was concentrated and then recrystallized in petroleum ether to obtain intermediate H as a white solid (460 g, yield 68%). 1H NMR (CDCl3, 400 MHz): δ 7.23˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.01 (s, 1H), 4.00 (s, 2H). the reaction was quenched with water The mixture was extracted with dichloromethane The organic layer was washed with an aqueous solution of saturated sodium bicarbonate with water, and then with brine, and dried over Na2SO4 The residue was concentrated recrystallized in petroleum ether

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[(5-bromo-2-chloro-phenyl)methyl]phenol 17b (2.0 g, 6.72 mmol, obtained from the synthetic method described in step 1 of example 17) and benzyl bromide (1.36 mL, 11.4 mmol) in tetrahydrofuran (20 mL) was added potassium carbonate (1.86 g, 13.4 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 25c as a white solid (1.83 g, 70.4%). The reaction mixture was quenched with saturated aqueous ammonium chloride extracted with ethyl acetate (50 mL×3) The combined organic layers were washed with saturated aqueous sodium chloride (50 mL×2) dried over anhydrous sodium sulfate filtered The filtrated was concentrated in vacuo the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[(5-bromo-2-chloro-phenyl)methyl]phenol 17b (2.0 g, 6.72 mmol, obtained from the synthetic method described in step 1 of example 17) and benzyl bromide (1.36 mL, 11.4 mmol) in tetrahydrofuran (20 mL) was added potassium carbonate (1.86 g, 13.4 mmol) at room temperature. The mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (50 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrated was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 25c as a white solid (1.83 g, 70.4%). The reaction mixture was quenched with saturated aqueous ammonium chloride extracted with ethyl acetate (50 mL×3) The combined organic layers were washed with saturated aqueous sodium chloride (50 mL×2) dried over anhydrous sodium sulfate filtered The filtrated was concentrated in vacuo the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[(5-bromo-2-chloro-phenyl)methyl]phenol 17b (23.4 g, 78.7 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (54.0 g, 394.0 mmol) at room temperature. The mixture was warmed up to 90° C. and stirred for 30 min, and then 2,2,2-trifluoroethyl-p-toluensulfonate (20 g, 78.7 mmol) was added. The reaction mixture was warmed up to 140° C. and stirred for 12 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was partitioned between ethylacetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE to give the title compound 17c as a white solid (26.0 g, 87.2%, HPLC: 97.45%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.54 (d, 1H), 7.45 (m, 1H), 7.40 (d, 1H), 7.18 (d, 2H), 7.00 (d, 2H), 4.80-4.64 (m, 2H), 4.01 (s, 2H). The reaction mixture was warmed up to 140° C. stirred for 12 hours The mixture was cooled to room temperature filtered The filtrate was concentrated in vacuo the residue was partitioned between ethylacetate (200 mL) and water (200 mL) The aqueous layer was extracted with ethyl acetate (100 mL×2) The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2) dried over anhydrous sodium sulfate filtered The filtrate was concentrated in vacuo the residue was purified by silica gel chromatography eluted with PE

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-[(5-bromo-2-chloro-phenyl)methyl]phenol 17b (23.4 g, 78.7 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (54.0 g, 394.0 mmol) at room temperature. The mixture was warmed up to 90° C. and stirred for 30 min, and then 2,2,2-trifluoroethyl-p-toluensulfonate (20 g, 78.7 mmol) was added. The reaction mixture was warmed up to 140° C. and stirred for 12 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was partitioned between ethylacetate (200 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE to give the title compound 17c as a white solid (26.0 g, 87.2%, HPLC: 97.45%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.54 (d, 1H), 7.45 (m, 1H), 7.40 (d, 1H), 7.18 (d, 2H), 7.00 (d, 2H), 4.80-4.64 (m, 2H), 4.01 (s, 2H). The reaction mixture was warmed up to 140° C. stirred for 12 hours The mixture was cooled to room temperature filtered The filtrate was concentrated in vacuo the residue was partitioned between ethylacetate (200 mL) and water (200 mL) The aqueous layer was extracted with ethyl acetate (100 mL×2) The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2) dried over anhydrous sodium sulfate filtered The filtrate was concentrated in vacuo the residue was purified by silica gel chromatography eluted with PE